PARENT AWARD R35GM118027 SUMMARY Tissue damage and repair represent fundamental problems in human health. Wound repair involves the integration of complex networks at both the single cell and multi-cellular level. These networks involve changes in gene expression, cell signaling and motility, and/or the physical properties of the environment that must be integrated to allow for wound healing. Despite progress in understanding the signals that mediate wound repair, there is a significant gap in understanding how different types of cells communicate to integrate a wound healing response. This gap limits our ability to design new therapeutic strategies for a broad range of human disease including cardiovascular disease, cancer, lung disease, tissue fibrosis, immune disorders and rheumatologic disease. The focus of my research is to understand the basic molecular mechanisms that regulate cell migration and how defects in cell migration contribute to human disease in the context of tissue damage and repair. My laboratory has developed the tools to simultaneously image and manipulate epithelial, macrophage and neutrophil responses to localized tissue damage in zebrafish. The optical transparency and ease of genetic manipulation make zebrafish an ideal model system to dissect multi-cellular and tissue interactions during wound repair. Understanding how wound repair is orchestrated and integrated at both the single cell and multi-cellular level in the context of different types of damage is the focus of our future research. These questions will be addressed using optogenetic tools, genomic approaches and advanced imaging in zebrafish and in vitro analysis using human cells. The overall aim of the proposal is to identify key pathways and cross talk that mediate cell migration during wound repair, dissect how they are altered in pathological conditions and ultimately may be targeted to understand and treat human disease.